Process for preparing tetrazole-5-carboxylic acid derivatives

ABSTRACT

A process for preparing a compound of structure (I) or a hydrate or solvate thereof in which R 1  is C 1-6  alkyl, optionally substituted phenyl or optionally substituted phenylC 1-6  alkyl, which comprises reacting an azide of the structure (II): M.sup.⊕ N 3 .sup.⊖ with a cyanoformate of the structure (III): NC.CO 2  R 1  in which M is an alkali metal atom, and R 1  is as described for structure (I), to form an intermediate salt of structure (IV), in which R 1  is as described for structure (I) and M is as described for structure (II) followed by conversion of the salt (IV) to the free tetrazole (I) or to a hydrate or solvate thereof.

This application is A 371 of PCT/EP94/00 305 filed Feb. 1, 1994.

The present invention relates to a novel process for preparing certaintetrazole compounds which are of use in the preparation oftherapeutically active substances, in particular certain benzopyrancompounds useful as inhibitors of 5-α-reductase and as leukotrieneantagonists. The invention further relates to novel salt forms of thetetrazole compounds and to a process for preparing them.

Benzopyran compounds substituted by a tetrazole ring are described inthe art, for example in EP 0173156-A. In addition, unpublished BritishPatent Application No. 9224922.6, filed 27 Nov. 1992, discloses a newprocess for preparing certain of the compounds of EP 0173156-A, inparticular compounds of structure (A): ##STR1## in which

R¹ is, inter alia, C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl or acarboxylic group, X is oxygen or sulphur and R² and R³ are, for example,hydrogen, by cyclisation of the corresponding intermediate compounds ofstructure (B): ##STR2## Compounds of structure (B) are described asbeing prepared by reaction of compounds of structure (C): ##STR3## witha tetrazole derivative of structure (D): ##STR4## or salts thereof, inwhich Z is a leaving group. The compounds (D), for example where Z is ani-butoxy group, are described as being prepared from the correspondingtetrazole-5-carboxylic disodium salt by reaction with i-butylchloroformate, followed by workup under acidic conditions. Preparationof salts of compounds (D) is not specifically described in GB 9224922.6although, for example, the preparation of the sodium salt ofethyl-5-tetrazole carboxylate, in solution only, is described in theliterature (Australian Journal of Chemistry (1984) 37, 2453-2468). Inparticular, the process described in GB 9224922.6 is used to prepare thecompounds of structure (A1): ##STR5##

It has now been found that, by using novel methods described herein, thetetrazole compounds (D) and the salts thereof can be prepared in highyield and in high purity, avoiding the undesirable azide by-productsassociated with known methods.

The present invention therefore produces, in a first aspect, a processfor preparing a compound of structure (I): ##STR6## or a hydrate orsolvate thereof in which R¹ is C₁₋₆ alkyl, optionally substituted phenylor optionally substituted phenylC₁₋₆ alkyl, which comprises combining anazide of structure (II) M.sup.⊕ N₃.sup.⊖ in which M is an alkali metalatom, with a compound of structure (III) NC.CO₂ R¹ in which R¹ is asdescribed for structure (I), to form an intermediate compound ofstructure (IV): ##STR7## in which R¹ is as described for structure (I)and M is as described for structure (II), followed by conversion of thesalt (IV) to the free tetrazole (I) or to a hydrate or solvate thereof.

Suitably, R¹ is C₁₋₆ alkyl, optionally substituted phenyl or optionallysubstituted phenylC₁₋₆ alkyl Preferably, R¹ is C₁₋₆ alkyl, for example,methyl, ethyl, i-butyl or t-butyl.

Suitably, alkali metal atoms M include lithium, sodium and potassium.Preferably M is sodium or potassium.

Suitably, the reaction between the compounds of structures (II) and(III) is carried out in a suitable solvent in the presence of an acid,at a temperature of between ambient and reflux temperature of thesolvent used, for as long as is required to take the reaction tocompletion. Suitable solvents include 2,6-lutidine and suitable acidsinclude trifluoroacetic acid.

This process for preparing the tetrazole derivatives of structure (I)proceeding via the intermediate salts (IV) provides a more efficient andsafer method of preparing compounds (I) than has been known before.Preparation of the tetrazole derivatives as described in EP 0323885 is alow yielding method and that described in Chem. Ber. (1975) 108, 887 isa very cumbersome method involving potential hazardous steps such asevaporation to dryness which makes them unsuitable for large scale use.In the present process, the salts (IV) readily precipitate out from themixture, leaving behind undesirable hazardous by-products (and anyunreacted starting materials which may be re-used in subsequentreactions) and can then be converted to the high purity tetrazoles (I).The conversion of the salts (IV) to the tetrazoles (I) can beaccomplished, for example, by treatment with an acid, such as dilute HClas described hereinafter in the Examples.

The preparation of tetrazoles of structure (I) via the salts (IV) is avery efficient process and provides a broad general process for thepreparation of salts of tetrazoles of structure (I) by providing aconvenient, safe and efficient preparation of the `free` tetrazoles ofstructure (I).

The present invention therefore provides in a further aspect a processfor preparing a compound of structure (V): ##STR8## in which R¹ is C₁₋₆alkyl, optionally substituted phenyl or optionally substitutedphenylC₁₋₆ alkyl, and X is an ion, characterised in that the compound isin solid form which comprises reacting a compound of structure (I) witha compound providing the source of the ion X.

Suitable and preferred groups R¹ are as described for structure (I).Suitable ions X include, for example, alkali metal ions such as lithium,sodium or potassium; group II ions such as calcium and magnesium; andammonium ions of structure N⁺ (R)₃ in which each group R is hydrogen orC₁₋₆ alkyl, provided that all three R groups cannot be hydrogen. Othergroups X will be apparent to those skilled in the art.

Suitable compounds providing the source of ion X will be apparent tothose skilled in the art, and include, for example, alkali metalalkoxides such as sodium methoxide, and soluble ion alkanoate salts suchas salts of alkyl-2-hexanoic acids, in particular sodium or potassiumethyl hexanoate as hereinafter described. Alternative ion sourcesinclude, for example, alkali metal halides such as sodium iodide, alkalimetal acetates such as sodium trifluoroacetate, and ion exchange resinsloaded with the ion X as appropriate.

It will be apparent to those skilled in the art that the salts (V) cannot only be prepared from the free tetrazoles (I) but can also beprepared by conversion from a different salt (V), for example via anionexchange using a suitable anion exchange resin. Thus, the source of ionX can, in practice, also be a compound of structure (V) itself.

It has been found that the salts of structure (I) can be isolated insolid form and as such are very stable and can be readily transported inpure form.

In a still further aspect there is therefore provided compounds ofstructure (V): ##STR9## or a hydrate or solvate thereof, in which R¹ isC₁₋₆ alkyl, optionally substituted phenyl or optionally substitutedphenylC₁₋₆ alkyl, and X is an ion, characterised in that the compound(V) is in solid form. Suitable values of R¹ and X are as describedabove.

The following examples serve to illustrate the invention. Temperaturesare recorded in degrees centigrade.

EXAMPLE 1 Anhydrous sodium salt of ethyl-5-tetrazole carboxylatestarting from ethyl cyanoformate.

2,6-Lutidine (115 ml) was stirred under nitrogen and trifluoroaceticacid (20.5 ml) added cautiously over 15 minutes, maintaining thetemperature at +5° to +10° C. by cooling in an ice bath. Powdered sodiumazide (17.8 g) was added, followed by ethyl cyanoformate (24.8 g) andthe reaction mixture heated slowly to ca. 80° C. The mixture was stirredat 75° to 80° C. for 5.5 hours, allowed to cool to room temperature andfiltered. The white crystals were washed with ethyl acetate (3×50 ml)and dried in vacuo to constant weight.

Yield of sodium salt: 34.37 g (83.8%)

Purity by hplc analysis: 95.3% as sodium salt

Azide content: none detected, <0.1%.

EXAMPLE 2 Purified ethyl-5-tetrazole carboxylate

The intermediate sodium salt (equivalent to 33 g of pure material),prepared as described in Example 2(a), was suspended in a mixture ofsaturated brine (100 ml) and ethyl acetate (100 ml), and sodium nitrite(5.2 g) added. The mixture was cooled to ca. 10° C. and cautiouslytreated with concentrated hydrochloric acid (60 ml) with ice cooling.Further sodium chloride was added to saturate the aqueous phase.

The phases were separated and the aqueous phase further extracted withethyl acetate (2×50 ml). The combined ethyl acetate phases wereevaporated on a rotary evaporator to about 65 g and treated with toluene(65 g). The mixture was again evaporated to about 65 g to give asuspension of the product as a crystalline solid. This was collected byfiltration, washed with toluene and dried.

Yield 25.6 g (89.6%)

Purity by hplc analysis 99.5% as free ester

EXAMPLE 3 Potassium salt of ethyl-5-tetrazole carboxylate starting fromethyl cyanoformate

a) Intermediate sodium salt

2,6-Lutidine (115 ml) was stirred under nitrogen and cooled in an icebath. Trifluoroacetic acid (20.5 ml) was added cautiously over 15minutes, maintaining the temperature at +5° to +12° C., followed bysodium azide (17.8 g) and the mixture stirred well. Ethyl cyanoformate(24.8 g) was then added over about 2 minutes and the reaction mixtureheated slowly to ca. 80° C. The mixture was stirred at 75° to 80° C. for3.5 hours, allowed to cool to room temperature and filtered. The whitecrystals were washed with ethyl acetate (4×20 ml) and dried in vacuo.

Yield of sodium salt: 34.0 g (82.9%)

Purity by hplc analysis: 95.5% as sodium salt

b) Conversion to the potassium salt

The sodium salt prepared in a) contained a trace of unreacted sodiumazide and small amounts of other impurities. These were removed and thematerial converted to the potassium salt as follows:

The intermediate sodium salt (14 g) was dissolved in ice-cold water (50ml) and treated with sodium nitrite (1.5 g). A mixture of conc.hydrochloric acid (15 ml) and water (35 ml) was then added slowly,keeping the temperature below 5° C. The mixture was stirred for 15minutes, then treated with urea (1.6 g) to destroy the excess nitrousacid. When gas evolution had subsided the solution was saturated withsodium chloride (30 g) and extracted with ethyl acetate (100 ml). Theaqueous phase was further extracted with ethyl acetate (2×50 ml) and thecombined ethyl acetate extracts washed with saturated brine (50 ml) anddried by stirring with magnesium sulphate (30 g) for 30 minutes.

The mixture was filtered, the drying agent washed with ethyl acetate andthe combined filtrate and washings treated slowly with a 2.16M solutionof potassium-2-ethyl hexanoate in 2-propanol (50 ml). The mixture wasstirred for 10 minutes, the crystals collected by filtration, washedwith ethyl acetate (3×25 ml) and dried in vacuo to constant weight.

Yield 12.9 g

Purity by hplc analysis 99.9% as potassium salt.

EXAMPLE 4 Crystalline hydrate of the sodium salt of ethyl-5-tetrazolecarboxylate, starting from ethyl cyanoformate

a) Intermediate sodium salt

2,6-Lutidine (100 ml) was stirred under nitrogen, and cooled in anice-bath. Trifluoroacetic acid (5.0 ml) was added cautiously over 15minutes, maintaining the temperature at +5° to +12° C., followed bysodium azide (17.8 g) and the mixture stirred well for 15 minutes. Ethylcyanoformate (24.8 g) was then added over about 3 minutes and thereaction mixture heated slowly to ca. 80° C. After an initial exothermin which the temperature reached 94° C., the mixture was stirred at 80°C. for 4.0 hours, cooled to room 10° C. and filtered. The white crystalswere washed with a little 2,6-lutidine, then slurried with ethyl acetate(130 ml). The product was filtered, washed with ethyl acetate (50 ml)and dried in vacuo.

Yield of sodium salt: 39.4 g (96.0%)

Purity by hplc analysis: 90.0% as sodium salt

b) Sodium salt hydrate

The sodium salt (30 g) and sodium nitrite (1.75 g) were dissolved inwater (75 ml), covered with ethyl acetate (100 ml) and cooled 10° C. 2Mhydrochloric acid (120 ml) was then added slowly with stirring, and themixture stirred for 30 minutes, allowing the temperature to rise to 20°C. The phases were separated, the aqueous phase saturated with sodiumchloride and further extracted with ethyl acetate (3×50 ml). Thecombined ethyl acetate phases were treated slowly with a solution ofsodium-2-ethyl hexanoate (31.0 g) in ethyl acetate (100 ml) toprecipitate the product as fine needles. These were collected, washedwith ethyl acetate, and dried in air.

The product was shown to be crystalline by X-ray powder diffraction.Peaks were recorded from 2.5 to 34.5 degrees 2 theta. The followingsignificant d values were observed (Å units):

14.418,8.277,7.210,7.030,5.460,4.983,4.811,4.613,4.391,4.086,3.880,3.686,3.532,3.289,3.163,3.090,2.922,2.741 and 2.672

The infra-red spectrum was significantly different from that of theproduct of Example 1, and showed strong bands assigned to bound water at3565 and 3935cm⁻¹.

Yield: 31.8 g

Purity by hplc analysis: 81.9% as sodium salt [theory for dihydrate82%].

EXAMPLE 5 Anhydrous sodium salt of ethyl-5-tetrazole carboxylate fromthe hydrate

The hydrate from Example 4 was dried in vacuo, with a loss in weight of17.7%. The product gave an infra-red spectrum indistinguishable fromthat of the product of Example 7.

EXAMPLE 6 Anhydrous sodium salt of ethyl-5-tetrazole carboxylate fromthe isolated ester and sodium ethoxide

Sodium ethoxide in ethanol (3.56 g of a 21% wt/wt solution) was addeddropwise to a solution of ethyl-5-tetrazole carboxylate (1.55 g) indiethyl ether (10 ml) and the mixture stirred for 18 hours at roomtemperature. The mixture was chilled, stirred for 20 minutes, andfiltered. The product was washed on the filter with cold ether anddried.

Yield 1.64 g

Purity by hplc analysis: 93% as sodium salt.

EXAMPLE 7 Anhydrous sodium salt of ethyl-5-tetrazole carboxylate fromthe isolated ester and sodium-2-ethyl hexanoate

Ethyl-5-tetrazole carboxylate (5.0 g) was dissolved in ethyl acetate(40ml) and treated with a solution of sodium-2-ethyl hexanoate (6.5 g)in ethyl acetate (15 ml) over about 30 minutes with stirring at roomtemperature. The white suspension was diluted with ethyl acetate (50 ml)and filtered. The product was washed on the filter with ethyl acetateand dried in vacuo over phosphorous pentoxide.

Yield 5.60 g (97%)

The product was shown to be crystalline by X-ray powder diffraction.Peaks were recorded from 2.5 to 34.5 degrees 2 theta. The followingsignificant d values were observed (Å units):

7,039,6.135,5.467,4.989,4.613,4.087,3.688,3.533,3.395,3.165,3.080,2.968,2.742and 2.673

Infra-red spectrum (nujol mull): Characteristic strong bands wereobserved at 1735, 1728 and 1718 cm⁻¹, (ester carbonyl) and at1239,1220,1174,1158,1059, 1041 and 1028 cm⁻¹.

    ______________________________________                                        Elemental analysis:                                                           ______________________________________                                        Requires                                                                             C 29.28%  H 3.07%   N 34.14% Na 14.01%                                 Found  C 29.08%  H 2.98%   N33.84%  Na 14.10%                                 ______________________________________                                    

Purity by hplc analysis: 100% as sodium salt.

EXAMPLE 8 Potassium salt of ethyl-5-tetrazole carboxylate from theisolated ester and potassium-2-ethyl hexanoate

Ethyl-5-tetrazole carboxylate (5.0 g) was dissolved in ethyl acetate(150 ml) and treated with a 2.16M solution of potassium-2-ethylhexanoate in 2-propanol (20 ml) over about 2 minutes with stirring atroom temperature. The addition was interrupted briefly to allow theproduct to crystallise. The product was viewed under a polarisingmicroscope and found to consist of rectangular prisms. These werecollected by filtration, washed on the filter with ethyl acetate (25 ml,50 ml) and dried in air.

Yield 6.0 g (94.6%)

Purity by hplc analysis: 99.70% as potassium salt

The product was shown to be crystalline by X-ray powder diffraction.Peaks were recorded from 2.5 to 34.5 degrees 2 theta. The followingsignificant d values were observed (Å units):

10.793,7.632,7.431,7.107,6.503,5.917,5.236,4.808,4.291,3.994,3.821,3.757,3.714,3.610,3.553,3.435,3.298,3.229,3.166,3.098,3.046,3.010,2.870,2.774 and 2.646

Infra-red spectrum (nujol mull):

Characteristic strong bands were observed at 1718 and 1706 cm⁻¹, (estercarbonyl) and at 1232, 1169,1157,1058,1042 and 1020 cm⁻¹.

We claim:
 1. A process for preparing a compound of structure (I):##STR10## or a hydrate or solvate thereof in which R¹ is C₁₋₆ alkyl,optionally substituted phenyl or optionally substituted phenylC₁₋₆alkyl, which comprises reacting an azide of structure (II) with acyanoformate of structure (III)

    M.sup.⊕ N.sub.3.sup.⊖                          (II)

    NC.CO.sub.2 R.sup.1                                        (III)

in which M is an alkali metal atom, and R¹ is as described for structure(I), to form an intermediate salt of structure (IV): ##STR11## in whichR¹ is as described for structure (I) and M is as described for structure(II) followed by conversion of the salt (IV) to the free tetrazole (I)or to a hydrate or solvate thereof.
 2. A process according to claim 1 inwhich R¹ is C₁₋₄ alkyl.
 3. A process according to claim 2 in which M isselected from sodium or potassium.
 4. A compound of structure (V):##STR12## or a solvate or hydrate thereof in which R¹ is C₁₋₆ alkyl,optionally substituted phenyl or optionally substituted phenylC₁₋₆alkyl, and X is an ion, in solid form, provided that X is not an ion offormula N⁺ (R)₃ in which each group R is hydrogen.
 5. A compoundaccording to claim 4 in which X is an alkali metal atom.
 6. A compoundaccording to claim 5 in which X is sodium or potassium.
 7. A process forpreparing a compound of structure (V) which comprises reacting acompound of structure (I) with a compound providing a suitable source ofthe ion X.
 8. A process according to claim 7 in which the compoundproviding the source of the ion X is 2-ethyl hexanoic acid.